Ciprofloxacin (The Merck Index 11th Edition, No.2315) is known as one of quinolone-type synthetic antibacterial agents that have cyclopropyl group at the 1-position of quinoline structure. A number of compounds with modifications at 5, 7, and 8-positions of this compound have been synthesized in order to improve antibacterial activity, physicochemical properties, e.g., water solubility, and safety of ciprofloxacin. For example, the Japanese Patent Unexamined Publication (KOKAI) No. (Sho)62-215572/1987 discloses the compound as set out below in which a piperazinyl group is introduced at the 7-position of the quinoline structure that has amino group at the 5-position and methyl group at the 8-position. However, a compound has not yet been known in which 3-amino-4-methyl (or ethyl)-pyrrolidinyl group is introduced at the 7-position of the quinoline structure having amino group at the 5-position and methyl group at the 8-position. ##STR2##
Although the quinolone-type synthetic antibacterial agents so far reported have potent antibacterial activities, they have problems from a viewpoint of safety, for example, phototoxicity, induction of chromosomal aberration, and induction of convulsion. These problems of the quinolone-type synthetic antibacterial agents are explained in each of the following literatures: Quinolone Antimicrobial Agents, 2nd edition, Chapter 26, Ed. By D. C. Hooper and J. S. Wolfson, American Society for Microbiology, Washington D.C., 1993, p.489 (phototoxicity, induction of chromosomal aberration, induction of convulsion and other); Mutagenicity Test (Henigen-sei Shiken) 2(3), p.154, 1993 (chromosomal aberration and other); and Environ. Mol. Mutagen., 13, p.238, 1989 (chromosomal aberration and other).
An object of the present invention is to provide quinolone-type synthetic antibacterial agents having high antibacterial activity, and in addition, whose adverse reactions such as phototoxicity, induction of chromosomal aberration, and induction of convulsion are reduced.
As for correlation between structures and adverse reactions of the quinolone-type synthetic antibacterial agents, the following general predictability has been noted in view of the state of the art: (A) as a substituent at the 8-position of a quinoline structure, a somewhat bulky substituent such as a chlorine atom or methyl group is preferred from a viewpoint of antibacterial activity; however, a compound having a chlorine atom at the 8-position has strong adverse reactions such as phototoxicity or induction of chromosomal aberration, and a compound having methyl group exhibits strong adverse reactions such as induction of chromosomal aberration; (B) amino group, halogen atoms, methyl group and the like have been used as a substituent at the 5-position of a quinoline structure; however, these substituents decrease antibacterial activity, or alternatively, increase adverse reactions such as phototoxicity or induction of chromosomal aberration; and (C) antibacterial activity is improved when one of 3-aminopyrrolidines is introduced as a substituent at the 7-position of a quinoline structure; however, adverse reactions such as induction of chromosomal aberration are increased.
The inventors of the present invention conducted various researches to achieve the foregoing object. As a result, they found that, contrary to the aforementioned general predictability, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives, in which amino group at the 5-position, methyl group at the 8-position, and 3-amino-4-methyl (or ethyl)-pyrrolidinyl group at the 7-position are substituted together, have potent antibacterial activities, and that the compounds are highly safe with reduced adverse reactions such as phototoxicity, induction of chromosomal aberration, and induction of convulsion. The Japanese patent application No. (Hei) 6-215213/1994 was filed on the basis of this invention.
The inventors of the present invention conducted further researches, and they consequently found that, among compounds that fall within the compounds of the aforementioned general formula, optically active compounds each having the substituent in a specific stereostructure have both excellent antibacterial activities and remarkably high safeties. The present invention was achieved on the basis of these findings.